The present invention relates to bisarylimidazolyl derivatives and pharmaceutical compositions comprising said derivatives which inhibit fatty acid amide hydrolase and are useful for the treatment of conditions affected by inhibiting fatty acid amide hydrolase.
Neuropathic pain is caused by injury to nerves as the result of many factors including physical damage (e.g., trauma, surgery), drugs such as Zidovudine (AZT), Carmustine (BCNU) and disease (e.g., diabetes, herpes zoster). The prevalence in the United States of neuropathies associated with diabetes, herpes and amputation is estimated at 1.5 million. The worldwide prevalence of diabetic neuropathy alone is expected to reach 12 million by 2007. Nerve injury can result in both allodynia and hyperalgesia.
Current treatment of neuropathic pain involves the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and acetaminophen) and other analgesics as well as anticonvulsants (e.g., carbamazepine, gabapentin) and tricyclic antidepressants (e.g., amitryptiline). Effective treatment of pain with current therapies is limited by adverse effects and a lack of efficacy against all components of pain.
Current research is aimed at understanding the molecular and physiological components of pain processing to develop more effective analgesics (Levine, J. D., New Directions in Pain Research: Meeting Report Molecules to Maladies, Neuron 20: 649-654, 1998; Pasternak, G. W., The Central Questions in Pain Perception May Be Peripheral, PNAS 95:10354-10355, 1998).
The analgesic properties of cannabinoids have been known for many years and to many cultures. Cannabinoids are active in many pre-clinical models of pain, including neuropathic pain. Within the last few years, several endogenous cannabinoids, including the fatty acid amides arachidonylethanolamide (anandamide), and arachidonyl amino acids such as N-arachidonylglycine, homo-xcex3-linolenyl-ethanolamide and docosatetraenyl-ethanolamide, as well as 2-arachidonyl-glycerol, have been shown to induce analgesia in laboratory animals (DeVane, W. A. et. al., Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptors, Science 258: 1946-1949, 1992; Hanus, L. et. al., Two New Unsaturated Fatty Acid Ethanolamides in Brain that Bind to the Cannabinoid Receptor, J. Med. Chem. 36: 3032-3034, 1993; Machoulam, R. et. al., Identification of an Endogenous 2-Monoglyceride, Present in Canine Gut, That Binds To Cannabinoid Receptors, Biochem. Pharmacol. 50: 83-90, 1995; Vogel, Z. et. al., Cannabinomimetic Behavioral Effects of and Adenylate Cyclase Inhibition By Two New Endogenous Anandamides, Eur. J. Pharmacol. 287: 145-152, 1995; Hargreaves, K. M. et al., Cannabinoids Reduce Hyperalgesia and Inflammation Via Interaction With Peripheral CB1 Receptors, Pain 75: 111-119, 1998; Rice, A. S. C., et. al., The Anti-Hyperalgesic Actions of the Cannabinoid Anandamide and the Putative CB2 Receptor Agonist Palmitoylethanolamide in Visceral and Somatic Inflammatory Pain, Pain 76: 189-199, 1998; Huang, S. M., et al., Identification of a New Class of Molecules, the Arachidonyl Amino Acids, and Characterization of One Member That Inhibits Pain, J. Biological Chemistry, 276: 46, 42639-42644, 2001). The ability of cannabinoid receptor antagonists and cannabinoid receptor antisense to induce hyperalgesia in animals suggests that endogenous cannabinoids regulate the nociceptive threshold (Hargreaves, K. M. et al., Hypoactivity of the Spinal Cannabinoid System Results in NMDA-Dependent Hyperalgesia, J. Neurosci. 18: 451-457, 1998; Piomelli, D. et. al., Control of Pain Initiation By Endogenous Cannabinoids, Nature 394: 277-281, 1998; Fields, H. L. et. al., An Analgesia Circuit Activated By Cannabinoids, Nature 395: 381-383, 1998). Elevation of levels of neuroactive fatty acid amides such as anandamide may provide a unique mechanism to achieve analgesia. The mechanisms by which endogenous cannabinoids are synthesized are not well understood; therefore, targets for drugs aimed at increasing the synthesis of these compounds are slow to be identified.
Anandamide and the other identified endogenous cannabinoids are inactivated through a cleavage mechanism by a membrane-bound enzyme, fatty acid amide hydrolase (FAAH). FAAH, therefore, provides an important target for regulating the activity of endogenous cannabinoids. The inhibition of FAAH may elevate levels of anandamide or other endogenous cannabinoids to increase the nociceptive threshold. Furthermore, the inhibition of FAAH would also extend the therapeutic benefits of other cannabinoid agonists in the treatment of emesis, anxiety, feeding behaviors, movement disorders, glaucoma, neuroprotection and cardiovascular disease.
Thus according to a first embodiment of the first aspect of the present invention are provided compounds of Formula (I) 
and pharmaceutically acceptable salts and solvates thereof
wherein
R1 are R2 are each independently H, C1-3alkyl or halo;
R3 is C1-C3alkyl or C3-7cycloalkyl;
A is C1-12alkylene or L;
L is -phenyl-Oxe2x80x94C1-4alkylene wherein said C1-4alkylene is attached to D;
provided that if A is L, then D is X(O)O and Axe2x80x94D is not interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene;
D is X(O)O, X(O)N(Gxe2x80x2), HYC(O)O or HYC(O)ONxe2x95x90C(Gxe2x80x2);
X is C and is attached to A;
Y is N and is attached to A;
G is H, C1-5alkyl, C1-5haloalkyl, C3-7cycloalkyl, phenyl, xe2x80x94C1-2alkylene-phenyl, C-pyridyl or N-pyridyl, said phenyl or xe2x80x94C1-2alkylene-phenyl are each optionally and independently substituted with one or more of the same or different substitutents selected from the group consisting of halo, NO2, CN, xe2x80x94C(O)Oxe2x80x94C1-3-alkyl, C1-3alkyl, hydroxy and C1-3alkoxy;
Gxe2x80x2 is H, C1-5alkyl or C1-5haloalkyl;
wherein Axe2x80x94D is optionally interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene;
xe2x80x83wherein
Z is O or S and is attached to A;
J is CH and is attached to A, D and Jxe2x80x2;
Jxe2x80x2 is C1-4alkyl or phenyl; and
provided that
if Axe2x80x94D is interrpted with xe2x80x94Z-phenyl-, then A is C1-5alkylene;
if Axe2x80x94D is not interrpted with xe2x80x94Z-phenyl-, then A is C5-12alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2are each H.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are each halo.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are each fluoro.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R3 is methyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R3is ethyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is L.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C3-10alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C7-10alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C4-8alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C5-7alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C8-9alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C9alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C6alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein A is C1-4alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein D is X(O)O.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein D is X(O)N(Gxe2x80x2).
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein D is HYC(O)O.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein D is HYC(O)ONxe2x95x90C(Gxe2x80x2).
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is C1-5alkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is C3-7cycloalkyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is xe2x80x94C1-2alkylene-phenyl.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is phenyl or xe2x80x94C1-2alkylene-phenyl, said phenyl or phenyl of said xe2x80x94C1-2alkylene-phenyl are optionally substituted with the same or different substitutents selected from the group consisting of halo, CN, xe2x80x94C(O)Oxe2x80x94C1-3-alkyl, C1-3alkyl and C1-3alkoxy.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is phenyl or xe2x80x94C1-2alkylene-phenyl, said phenyl or phenyl of said xe2x80x94C1-2alkylene-phenyl are substituted with halo, xe2x80x94C(O)Oxe2x80x94C1-3-alkyl, C1-3alkyl or C1-3alkoxy.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is phenyl or xe2x80x94C1-2alkylene-phenyl, said phenyl or phenyl of said xe2x80x94C1-2alkylene-phenyl are substituted with fluoro.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein G is phenyl or xe2x80x94C1-2alkylene-phenyl, said phenyl or phenyl of said xe2x80x94C1-2alkylene-phenyl are substituted with cyano.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein Axe2x80x94D are not interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein Axe2x80x94D are interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein Axe2x80x94D is interrupted with Jxe2x80x94Jxe2x80x2.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein Axe2x80x94D is interrupted with xe2x80x94Z-phenyl- .
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein Axe2x80x94D is interrupted with xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are each H, R3 is C1-3alkyl, A is C7-10alkylene, D is X(O)O and Axe2x80x94D is not interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are each H, R3 is C1-3alkyl, A is C1-5alkylene, D is X(O)O and Axe2x80x94D is interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are each H, R3 is C1-3alkyl, A is C7-10alkylene, D is X(O)N(Gxe2x80x2) and Axe2x80x94D is not interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are each H, R3is C1-3alkyl, A is C1-5alkylene, D is X(O)N(Gxe2x80x2) and Axe2x80x94D is interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are each H, R3 is C1-3alkyl, A is C7-10alkylene, D is HYC(O)O and Axe2x80x94D is not interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are each H, R3 is C1-3alkyl, A is C1-5alkylene, D is HYC(O)O and Axe2x80x94D is interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are each H, R3 is C1-3alkyl, A is C7-10alkylene, D is HYC(O)ONxe2x95x90C(Gxe2x80x2) and Axe2x80x94D is not interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided compounds of Formula (I) according to the first embodiment of the first aspect wherein R1 and R2 are each H, R3 is C1-3alkyl, A is C1-5alkylene, D is HYC(O)ONxe2x95x90C(Gxe2x80x2) and Axe2x80x94D is interrupted with Jxe2x80x94Jxe2x80x2, xe2x80x94Z-phenyl- or xe2x80x94Zxe2x80x94C1-3alkylene.
According to another embodiment of the first aspect of the present invention are provided [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
[6-(2-Ethyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid tert-butyl ester;
[6-(2-Ethyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid sec-butyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid benzyl ester;
2-Propanone,O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid methyl ester;
6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-fluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,4-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-chloro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-methoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid o-tolyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-cyano-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-methoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl-carbamic acid methyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid ethyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,4-difluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-chloro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-methoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid o-tolyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-cyano-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid ethyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,4-difluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-chloro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid o-tolyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-cyano-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-methoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 3,4-difluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2-fluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2,6-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid ethyl ester;
Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
4-Fluorobenzaldehyde,O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
2-Nitrobenzaldehye, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
4-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 3,4-difluoro-phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 4-chloro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 3,4-difluoro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 4-methoxy-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 4-chloro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2-methoxy-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 3-chloro-phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxyl-phenyl}-carbamic acid phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 2-fluoro-phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 4-fluoro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid 4-methoxy-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2-fluoro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2,6-difluoro-phenyl ester;
{4-[2-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-ethoxy]-phenyl}-carbamic acid ethyl ester;
[1-Methyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
[1-Ethyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
[1-Isopropyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester or
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-1-phenyl-hexyl]-carbamic acid 2-fluoro-phenyl ester.
According to another embodiment of the first aspect of the present invention are provided [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
2-Propanone,O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid cyclohexyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid methyl ester;
6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-fluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,4-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-chloro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-methoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid o-tolyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-cyano-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-methoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid methyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid ethyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,4-difluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-chloro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-methoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid o-tolyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-cyano-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid ethyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,4-difluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-chloro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid o-tolyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-cyano-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-methoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 3,4-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid isopropyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2-fluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2,6-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid ethyl ester;
Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
4-Fluorobenzaldehyde,O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
2-Nitrobenzaldehye, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
4-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 3,4-difluoro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 4-methoxy-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 4-chloro-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 2-methoxy-phenyl ester;
{4-[3-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-propoxy]-phenyl}-carbamic acid 3-chloro-phenyl ester;
[1-Methyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
[1-Ethyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
[1-Isopropyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester; or
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-1-phenyl-hexyl]-carbamic acid 2-fluoro-phenyl ester.
According to another embodiment of the first aspect of the present invention are provided [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
2-Propanone,O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-fluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,4-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-chloro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-methoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid o-tolyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-cyano-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid ethyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2,4-difluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-chloro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-methoxy-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid o-tolyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-cyano-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,4-difluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2-fluoro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-chloro-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-methoxy-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 4-cyano-phenyl ester;
[5-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-pentyl]-carbamic acid 2,6-dimethoxy-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 3,4-difluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2-fluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2,6-difluoro-phenyl ester;
Benzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
4-Fluorobenzaldehyde,O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
2-Nitrobenzaldehye, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
3-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
4-Nitrobenzaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
3-Pyridinecarboxaldehyde, O-[6-(2-methyl-4,5-diphenyl-1H-imidazol-1-yl)hexyl]amino]carbonyl]oxime;
[1-Methyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester; or
[1-Ethyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester.
According to another embodiment of the first aspect of the present invention are provided [6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester;
6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-fluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2,4-difluoro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 4-chloro-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid o-tolyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 2-fluoro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-chloro-phenyl ester;
[7-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-heptyl]-carbamic acid 4-cyano-phenyl ester;
[6-(2-Methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 3,4-difluoro-phenyl ester;
{6-[4,5-Bis-(4-fluoro-phenyl)-2-methyl-imidazol-1-yl]-hexyl}-carbamic acid 2-fluoro-phenyl ester; or
[1-Methyl-6-(2-methyl-4,5-diphenyl-imidazol-1-yl)-hexyl]-carbamic acid 2-fluoro-phenyl ester.
According to various embodiments of a second aspect of the present invention are provided pharmaceutical formulations comprising compounds of Formula (I) as defined herein.
According to various embodiments of a third aspect of the present invention are provided methods of treating conditions the treatment of which can be effected by the inhibitition of FAAH by the administration of pharmaceutical compositions comprising compounds of Formula (I) as defined herein.
According to another embodiment of the third aspect of the present invention is provided a method of treating pain, more particularly chronic pain, acute pain and neuropathic pain by the administration of pharmaceutical compositions comprising compounds of Formula (I) as defined herein.
According to another embodiment of the third aspect of the present invention is provided a method of treating pain, more particularly chronic pain, acute pain and neuropathic pain by the administration of a pharmaceutical composition comprising 
or salt or solvate thereof.
According to another embodiment of the third aspect of the present invention is provided a method of treating neuropathic pain by the administration of a pharmaceutical composition comprising 
or salt or solvate thereof.
According to another embodiment of the third aspect of the present invention is provided a method of providing neuroprotection and contraception and yet further methods of psychomotor disorder, hypertension, cardiovascular disease, eating disorder, nausea, AIDS-related complex, glaucoma, inflammation, psoriasis and multiple sclerosis by the administration of pharmaceutical compositions comprising compounds of Formula (I) as defined herein. See Raphael Mechoulam, xe2x80x9cLooking Back at Cannabis Research,xe2x80x9d Current Pharmaceutical Design, 2000, Vol. 6, No. 13, pp. 1313-1322 (p. 1319); Sumner H. Burstein, xe2x80x9cAjulemic Acid (CT3): A Potent Analog of the Acid Metabolites of THC,xe2x80x9d Current Pharmaceutical Design, 2000, Vol. 6, No. 13, pp. 1339-1345 (p. 1340); Vincenzo Di Marzo, et al., xe2x80x9cEndocannabinoids: New Targets for Drug Development,xe2x80x9d Current Pharmaceutical Design, 2000, Vol. 6, No. 13, pp. 1361-1380 (p. 1362); and Sonya L. Palmer, et al., xe2x80x9cNatural and Synthetic Endocannabinoids and Their Structure-Activity Relationships,xe2x80x9d Current Pharmaceutical Design, 2000, Vol. 6, No. 13, pp. 1381-1397 (p. 1386).
Other embodiments of the present invention may comprise a suitable combination of two or more of embodiments and/or aspects disclosed herein.
Yet other embodiments and aspects of the invention will be apparent according to the description provided below.